Lactam kinase inhibitors

ABSTRACT

Compounds useful as kinase inhibitors are provided herein, as well as salts, pharmaceutical compositions, methods of medical treatment and methods of synthesis thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/348,862, filed Nov. 10, 2016, which is a continuation of U.S.application Ser. No. 14/982,443, filed Dec. 29, 2015, which is adivisional of U.S. application Ser. No. 14/498,796, filed Sep. 26, 2014and issued as U.S. Pat. No. 9,260,442 on Feb. 16, 2016, which is acontinuation of PCT Application No. PCT/US2013/033971, filed Mar. 27,2013, which claims the benefit of provisional U.S. Application No.61/617,657, filed Mar. 29, 2012. The entirety of these applications ishereby incorporated by reference for all purposes.

FIELD OF THE INVENTION

The invention relates to novel compounds useful as kinase inhibitors inmedicine.

BACKGROUND OF THE INVENTION

A protein kinase inhibitor is a type of enzyme inhibitor thatspecifically blocks the action of one or more protein kinases. Proteinkinases are enzymes that add a phosphate (PO4) group to a protein orother organic molecule, usually on the serine, threonine, or tyrosineamino acid. Hence, protein kinase inhibitors can be subdivided orcharacterized by the amino acids whose phosphorylation is inhibited:most kinases act on both serine and threonine, the tyrosine kinases acton tyrosine, and a number (dual-specificity kinases) act on all three.There are also protein kinases that phosphorylate other amino acids,including histidine kinases that phosphorylate histidine residues.Phosphorylation is a necessary step in some cancers and inflammatorydiseases. Inhibiting the protein kinases can treat these diseases andprotein kinase inhibitors are used as drugs. Literature on the use ofkinases inhibitors in drug discovery includes “Targeting Protein Kinasesfor Cancer Therapy” by Mathew D. J et al, Publisher J. Wiley 2010 andalso “Protein Kinases as Drug targets” Klebl et al. J. Wiley 2011.

SUMMARY OF THE INVENTION

Compounds of formulae (Q) and (QQ) are provided as part of theinvention:

DETAILED DESCRIPTION OF THE INVENTION

A compound of the formulae (Q) or (QQ) above are part of the invention,wherein R²⁶ is H, C₁-C₆ alkyl, or haloalkyl, cycloalkyl or cycloalkylcontaining one or more heteroatoms selected from N, O, and S;

each R³¹ is independently aryl, alkyl, cycloalkyl or haloalkyl, whereineach of said alkyl, cycloalkyl and haloalkyl groups optionally includesO or N heteroatoms and two R³¹s on adjacent ring atoms or on the samering atom together with the ring atom(s) to which they are attachedoptionally form a 3-8-membered cycle;yy is 0, 1, 2, 3 or 4;ZZ is —(CH₂)_(xx)— wherein xx is 1, 2, 3 or 4 or —O—(CH₂)_(xx)— whereinxx is 2, 3 or 4;R⁵⁵ is NHR^(A), R^(A) is unsubstituted C₁-C₈ alkyl, cycloalkylalkyl, or-TT-RR, C₁-C₈ cycloalkyl or cycloalkyl containing one or moreheteroatoms selected from N, O, and S,TT is an unsubstituted or substituted C₁-C₈ alkyl or C₃-C₈ cycloalkyllinker; and RR is a hydroxyl, unsubstituted or substituted C₁-C₆ alkoxy,amino, unsubstituted or substituted C₁-C₆ alkylamino, unsubstituted orsubstituted di-C₁-C₆ alkylamino, unsubstituted or substituted C₆-C₁₀aryl, unsubstituted or substituted heteroaryl comprising one or two 5-or 6-member rings and 1-4 heteroatoms selected from N, O and S,unsubstituted or substituted C₃-C₁₀ carbocycle, or unsubstituted orsubstituted heterocycle comprising one or two 5- or 6-member rings and1-4 heteroatoms selected from N, O and S;R⁷⁷ is -(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl,-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵,-(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any ofwhich may be optionally independently substituted with one or more R^(x)groups as allowed by valance, and wherein two R^(x) groups bound to thesame or adjacent atoms may optionally combine to form a ring;R³ and R⁴ at each occurrence are independently:(i) hydrogen or(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl,heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may beoptionally independently substituted with one or more R^(x) groups asallowed by valance, and wherein two R^(x) groups bound to the same oradjacent atom may optionally combine to form a ring; or R³ and R⁴together with the nitrogen atom to which they are attached may combineto form a heterocyclo ring optionally independently substituted with oneor more R^(x) groups as allowed by valance, and wherein two R^(x) groupsbound to the same or adjacent atoms may optionally combine to form aring;R⁵ and R⁵* at each occurrence is:(i) hydrogen, or(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any ofwhich may be optionally independently substituted with one or more R^(x)groups as allowed by valance;R^(x) at each occurrence is independently, halo, cyano, nitro, oxo,alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkyl, -(alkylene)_(m)-OR⁵,-(alkylene)_(m)-O-alkylene-OR⁵, -(alkylene)_(m)-S(O)_(n)-R⁵,-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-CN, -(alkylene)_(m)-C(O)—R⁵,-(alkylene)_(m)-C(S)—R⁵, -(alkylene)_(m)-C(O)—OR⁵,-(alkylene)_(m)-O—C(O)—R⁵, -(alkylene)_(m)-C(S)—OR⁵,-(alkylene)_(m)-C(O)-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(S)—NR³R⁴,-(alkylene)_(m)-N(R³)—C(O)—NR³R⁴, -(alkylene)_(m)-N(R³)—C(S)—NR³R⁴,-(alkylene)_(m)-N(R³)—C(O)—R⁵, -(alkylene)_(m)-N(R³)—C(S)—R⁵,-(alkylene)_(m)-O—C(O)—NR³R⁴, -(alkylene)_(m)-O—C(S)—NR³R⁴,-(alkylene)_(m)-SO₂—NR³R⁴, -(alkylene)_(m)-N(R³)—SO₂—R⁵,-(alkylene)_(m)-N(R³)—SO₂—NR³R⁴, -(alkylene)_(m)-N(R³)—C(O)—OR⁵)-(alkylene)_(m)-N(R³)—C(S)—OR⁵, or -(alkylene)_(m)-N(R³)—SO₂—R⁵;wherein:said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkyl groups may be furtherindependently substituted with one or more-(alkylene)_(m)-CN, -(alkylene)_(m)-OR⁵*, -(alkylene)_(m)-S(O)_(n)—R⁵*,-(alkylene)_(m)-NR³*R⁴*, -(alkylene)_(m)-C(O)—R⁵*,-(alkylene)_(m)-C(═S)R⁵*, -(alkylene)_(m)-C(═O)O R⁵*,-(alkylene)_(m)-OC(═O)R⁵*, -(alkylene)_(m)-C(S)—OR⁵*,-(alkylene)_(m)-C(O)—NR³*R⁴*, -(alkylene)_(m)-C(S)—NR³*R⁴*,-(alkylene)_(m)-N(R³*)—C(O)—NR³*R⁴*,-(alkylene)_(m)-N(R³*)—C(S)—NR³*R⁴*, -(alkylene)_(m)-N(R³*)—C(O)—R⁵*,-(alkylene)_(m)-N(R³*)—C(S)—R⁵*, -(alkylene)_(m)-O—C(O)—NR³*R⁴*,-(alkylene)_(m)-O—C(S)—NR³*R⁴*, -(alkylene)_(m)-SO₂—NR³*R⁴*,-(alkylene)_(m)-N(R³*)—SO₂—R⁵*, -(alkylene)_(m)-N(R³*)—SO₂—NR³*R⁴*,-(alkylene)_(m)-N(R³*)—C(O)—OR⁵*, -(alkylene)_(m)-N(R³*)—C(S)—OR⁵*, or-(alkylene)_(m)-N(R³*)—SO₂—R⁵*,n is 0, 1 or 2, andm is 0 or 1; andR³* and R⁴* at each occurrence are independently:(i) hydrogen or(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any ofwhich may be optionally independently substituted with one or more IVgroups as allowed by valance; or R³* and R⁴* together with the nitrogenatom to which they are attached may combine to form a heterocyclo ringoptionally independently substituted with one or more IV groups asallowed by valance; andR²⁷ is -(alkylene)_(m)-C₃-C₈ cycloalkyl, -(alkylene)_(m)-aryl,-(alkylene)_(m)-heterocyclo, -(alkylene)_(m)-heteroaryl,-(alkylene)_(m)-NR³R⁴, -(alkylene)_(m)-C(O)—NR³R⁴; -(alkylene)_(m)-O—R⁵,-(alkylene)_(m)-S(O)_(n)—R⁵, or -(alkylene)_(m)-S(O)_(n)—NR³R⁴ any ofwhich may be optionally independently substituted with one or more IVgroups as allowed by valance, and wherein two IV groups bound to thesame or adjacent atoms may optionally combine to form a ring, providingthat in (Q), R²⁷ may also be H, C₁-C₃ alkyl or haloalkyl, or apharmaceutically acceptable salt thereof. In some specific cases, aryl,such as phenyl, or heteroaryl can be ortho alkyl, cycloalkyl, halo,haloalkyl, thioalkyl, sulfonylalkyl, or aminodialkyl. Aryl andheteroaryl could also be ortho-disubstitued with alkyl, cycloalkyl,halo, haloalkyl, thioalkyl, sulfonylalkyl, or aminodialkyl as allowed byvalence. Aryl and heteroaryl could also be meta or para substituted withalkyl, cycloalkyl, haloalkyl, halo, haloalkyl, thioalkyl, sulfonylalkyl,or aminoalkyl.

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg (2007) “Advanced Organic Chemistry 5^(th) Ed.” Vols.A and B, Springer Science+Business Media LLC, New York. The practice ofthe present invention will employ, unless otherwise indicated,conventional methods of synthetic organic chemistry, mass spectroscopy,preparative and analytical methods of chromatography, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology

The term “alkyl,” either alone or within other terms such as “haloalkyl”and “alkylamino,” embraces linear or branched radicals having one toabout twelve carbon atoms. “Lower alkyl” radicals have one to about sixcarbon atoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,hexyl and the like.

The term “alkylene” embraces bridging divalent alkyl radicals. Examplesinclude methylene, ethylene, propylene, isopropylene and the like.

“Alkenyl” embraces linear or branched radicals having at least onecarbon-carbon double bond of two to about twelve carbon atoms. “Loweralkenyl” radicals having two to about six carbon atoms. Examples ofalkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl,” embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

“Alkynyl” denotes linear or branched radicals having at least onecarbon-carbon triple bond and having two to about twelve carbon atoms.“Lower alkynyl” radicals may have two to about six carbon atoms.Examples of such radicals include propargyl, butynyl, and the like.

Alkyl, alkenyl, and alkynyl radicals may be optionally substituted withone or more functional groups such as halo, hydroxy, nitro, amino,cyano, haloalkyl, aryl, heteroaryl, heterocyclo, etc.

“Alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino” where aminogroups are independently substituted with one alkyl radical and with twoalkyl radicals, respectively. “Lower alkylamino” radicals have one ortwo alkyl radicals of one to six carbon atoms attached to a nitrogenatom. Suitable alkylamino radicals may be mono or dialkylamino such asN-methylamino, N-ethylamino, N.N-dimethylamino, N,N-diethylamino and thelike.

“Halo” means halogens such as fluorine, chlorine, bromine or iodineatoms.

“Haloalkyl” embraces radicals wherein any one or more of the alkylcarbon atoms is substituted with one or more halo as defined above.Examples include monohaloalkyl, dihaloalkyl and polyhaloalkyl radicalsincluding perhaloalkyl. A monohaloalkyl radical, for one example, mayhave either an iodo, bromo, chloro or fluoro atom within the radical.Dihalo and polyhaloalkyl radicals may have two or more of the same haloatoms or a combination of different halo radicals. “Lower haloalkyl”embraces radicals having 1-6 carbon atoms. Examples of haloalkylradicals include fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

“Perfluoroalkyl” means alkyl having all hydrogen atoms replaced withfluoro atoms, eg trifluoromethyl and pentafluoroethyl.

“Aryl”, alone or in combination, means a carbocyclic aromatic systemcontaining one or two rings wherein such rings may be attached togetherin a fused manner. The term “aryl” embraces aromatic radicals such asphenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. Morepreferred aryl is phenyl. Said “aryl” group may have 1 or moresubstituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro,cyano, alkoxy, lower alkylamino, and the like. An aryl group may beoptionally substituted with one or more functional groups such as halo,hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycloand the like.

“Heterocyclyl” (or “heterocyclo”) embraces saturated, and partiallysaturated heteroatom-containing ring radicals, where the heteroatoms maybe selected from nitrogen, sulfur and oxygen. Heterocyclic ringscomprise monocyclic 6-8 membered rings, as well as 5-16 memberedbicyclic ring systems (which can include bridged fused and spiro-fusedbicyclic ring systems). It does not include rings containing —O—O—.—O—S—or —S—S— portions. Said “heterocyclyl” group may have 1 to 3substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl,lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino, and the like.Examples of saturated heterocyclo groups include saturated 3- to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl,and the like.

Particular examples of partially saturated and saturated heterocyclogroups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like. Heterocyclo groups also includesradicals where heterocyclic radicals are fused/condensed with arylradicals: unsaturated condensed heterocyclic group containing 1 to 5nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl, e.g., tetrazolo [1,5-b]pyridazinyl; unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms,e.g. benzoxazolyl, benzoxadiazolyl; unsaturated condensedheterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogenatoms, e.g., benzothiazolyl, benzothiadiazolyl; and saturated, partiallyunsaturated and unsaturated condensed heterocyclic group containing 1 to2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl].

The term “heteroaryl” denotes aryl ring systems that contain one or moreheteroatoms selected from the group O, N and S, wherein the ringnitrogen and sulfur atom(s) are optionally oxidized, and nitrogenatom(s) are optionally quarternized. Examples include unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated5- to 6-membered heteromonocyclic group containing an oxygen atom, forexample, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-memberedheteromonocyclic group containing a sulfur atom, for example, 2-thienyl,3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example,oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heteroarylalkyl” denotes alkyl radicals substituted with aheteroaryl group. Examples include pyridylmethyl and thienylethyl.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —C(O)—OH.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —C(O)—.

“Aminocarbonyl” denotes an amide group of the formula —C(O)—NH₂.

“Heterocycloalkyl” embraces heterocyclic-substituted alkyl radicals.Examples include piperidylmethyl and morpholinylethyl.

“Arylalkyl” embraces aryl-substituted alkyl radicals. Examples includebenzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

“Cycloalkyl” includes saturated carbocyclic groups of 3 to 10 carbons.Lower cycloalkyl groups include C₃-C₆ rings. Examples includecyclopentyl, cyclopropyl, and cyclohexyl. Cycloalkyl groups may beoptionally substituted with one or more functional groups such as halo,hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycloand the like.

“Cycloalkylalkyl” embraces cycloalkyl-substituted alkyl radicals. “Lowercycloalkylalkyl” radicals are cycloalkyl radicals attached to alkylradicals having one to six carbon atoms. Examples of includecyclohexylmethyl. The cycloalkyl in said radicals may be additionallysubstituted with halo, alkyl, alkoxy and hydroxy.

“Cycloalkenyl” includes carbocyclic groups having one or morecarbon-carbon double bonds including “cycloalkyldienyl” compounds.Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl andcycloheptadienyl.

“Comprising” is meant to be open ended, including the indicatedcomponent but not excluding other elements.

“Oxo” as used herein contemplates an oxygen atom attached with a doublebond. “Nitro” as used herein contemplates —NO₂. “Cyano” as used hereincontemplates —CN.

Particular values of R²⁶ are H, methyl, ethyl, n-propyl, cyclopropyl andsec-butyl; of R^(3′) are methyl, ethyl, n-propyl, iso-propyl,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; of yy are 0, 1 and2; of ZZ are —CH₂—, —CH₂CH₂, —C(CH₃)₂CH₂— reading from left to right orright to left and —CH₂CH(spriocyclopentyl or spriocyclohexyl)-readingfrom left to right or right to left in the depicted formulae; of R⁵⁵ arecis or trans 4-hydroxycyclohexylamino, cyclohexyl- or cyclopenylaminoand straight chain C₁-C₈ alkylamino; of R⁷⁷ are 1-morpholino,2-methyl-1-morpholino and 2,6-dimethyl-1-morpholino; of R³ and R⁴ are H,methyl, ethyl, cyclohexyl and R³ and R⁴ are alkyl and combine to form a5- or 6-membered ring; of R⁵ and R^(5*) are H, methyl, ethyl, n-propyland cyclopropylmethyl; of R^(x) are chloro, methyl, ethyl andcyclopentyl; of R^(3*) and R^(4*) are H, methyl, ethyl, iso-propyl,n-buten-2-yl and phenyl; and of R²⁷ are H, phenyl, ortho-methylphenyl,ortho, ortho-dimethylphenyl, para-ethylphenyl and ortho,para-dichlorophenyl. The disclosed compounds can be made by thefollowing general schemes:

In Scheme 2, Ref-1 is WO 2010/020675 A1; Ref-2 is WO 2005/040166 A1; andRef-3 is Schoenauer, K and Zbiral, E. Tetrahedron Letters 1983, 24, 573.

EXAMPLES

To a solution of 5-bromo-2,4-dichloropyrimidine 12.80 g (0.054 mole) inethanol 250 mL was added Hunig's base 12.0 mL followed by the additionof a solution of N-(tert-butoxycarbonyl)-1,2-diaminoethane 10 g (0.0624mole) in 80 mL ethanol. The contents were stirred overnight for 20 hrs.The solvent was evaporated under vacuum. Ethyl acetate (800 mL) andwater (300 mL) was added and the layers separated. The organic layer wasdried with magnesium sulfate and then concentrated under vacuum. Columnchromatography on silica gel using hexane/ethyl acetate (0-60%) affordedtert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate.LCMS (ESI) 351 (M+H).

To tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate 5 g (14.23mmole) in toluene (42 mL) and triethylamine (8.33 mL) under nitrogen wasadded triphenyl arsine (4.39 g), 3,3-diethoxyprop-1-yne (3.24 mL) andPddba (1.27 g). The contents were heated at 70 degrees for 24 hrs. Afterfiltration through celite, the crude reaction was columned usinghexane/ethyl acetate (0-20%) to afford the desired product. 3.9 g.Column chromatography of the resulting residue using hexane/ethylacetate (0-30%) afforded tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate.LCMS (ESI) 399 (M+H)

To a solution of the coupled product 3.9 g (0.00976 mole) in THF (60 mL)was added TBAF (68.3 mL, 7 eq). The contents were heated to 45 degreesfor 2 hrs. Concentration followed by column chromatography using ethylacetate/hexane (0-50%) afforded tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamateas a pale brown liquid (1.1 g). ¹HNMR (d6-DMSO) 8.88 (s, 1H), 6.95 (brs,1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29 (m, 2H), 3.59 (m, 4H), 3.34 (m,1H), 3.18 (m, 1H), 1.19 (m, 9H), 1.17 (m, 6H). LCMS (ESI) 399 (M+H).

To 0.1 g (0.00025 mole) of tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamatein acetonitrile (2 mL) was added 1,3-Diiodo-5,5-dimethylhydantoin (95mg, 1 eq), and solid NaHCO₃ (63 mg, 3 eq). Stir at room temperature for16 hrs. Filter, concentrate and then column with hexane/ethylacetate(0-50%) to afford tert-butylN-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamateas a pale yellow solid 0.03 g. LCMS (ESI) 525 (M+H).

To tert-butylN-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate(0.1 g, 0.19 mmole) in dioxane (3 mL) was added 2-Methylphenylboronicacid (28 mg), tetrakis(triphenylphosphine)palladium (25 mg) and 250 mgpotassium phosphate in 0.3 mL water. Heat in a CEM Discovery microwaveat 90° C. for 3 hrs. The crude reaction was loaded onto silica gel andcolumned using hexane/ethyl acetate (0-30%) to afford tert-butylN-[2-[2-chloro-6-(diethoxymethyl)-5-(o-tolyppyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate(0.06 g). LCMS (ESI) 489 (M+H).

To tert-butylN-[2-[2-chloro-6-(diethoxymethyl)-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate(0.85 g, 1.74 mmole) in AcOH (10 mL) was added water (1.5 mL), stir atroom temperature for 16 hrs. The crude reaction was then concentratedunder vacuum. After addition of ethyl acetate (50 mL) the organic layerwas washed with satd. NaHCO₃. The organic layer was dried with magnesiumsulfate and then concentrated under vacuum to afford the crudeintermediate, tert-butylN-[2-[2-chloro-6-formyl-5-(o-tolyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate.To this crude intermediate in DMF (5 mL) was added oxone (1.3 g). Afterstirring for 2.5 hrs, water (20 mL) and ethyl acetate (100 mL) wasadded. The organic layer was separated, dried and then concentratedunder vacuum to afford the crude product which was columned over silicagel using hexane/ethyl acetate (0-50%) to afford7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid (0.112 g). LCMS (ESI) 431 (M+H).

Intermediate (IN-1)

To 0.1 g (0.261 mmole) of7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid in DCM (4.1 mL) was added DMAP (20 mg) followed by the addition ofN,N′-Diisopropylcarbodiimide (0.081 mL, 2 eq). After stirring for 3 hrs,TFA (0.723 mL) was added. Stirring was then continued for another 30minutes. The reaction mixture was neutralized with satd. NaHCO₃. DCM (20mL) was then added and the organic layer separated, dried with magnesiumsulfate and then concentrated under vacuum to afford the crude productwhich was columned using hexane/ethylacetate (0-100%) to afford chlorotricyclic amide Intermediate (IN-1)(0.65 g). LCMS (ESI) 313 (M+H).

Compound (1)

To 0.040 g (0.128 mmole) of the chloro tricyclic amide (IN-1) in dioxane(2.5 mL) under nitrogen was added Pd₂(dba)₃ (12 mg), sodiumtert-butoxide (16 mg), BINAP (16 mg) 4-morpholinoaniline (22.7 mg, 1eq). The reaction mixture was heated at 90° C. in a CEM Discoverymicrowave for 3.0 hrs. The crude reaction was loaded on a silica gelcolumn and the contents eluted with DCM/MeOH (0-6%) to afford Compound(1) (10 mg). LCMS (ESI) 455 (M+H). 1H NMR (600 MHz, DMSO-d₆) δ ppm 2.14(s, 3H) 3.23-3.50 (m, 2H) 3.57-3.73 (m, 2H), 3.81-3.92 (m, 8H),7.11-7.31 (m, 4H) 7.31-7.48 (m, 1H) 7.58-7.73 (m, 1H) 7.77-7.95 (m, 2H)8.05-8.21 (m, 1H) 8.44 (s, 1H) 9.85-10.01 (m, 1H).

Compound (2)

To 0.024 g of the chloro tricyclic amide (IN-1)) inN-methyl-2-pyrrolidone (NMP) (1.5 mL) was addedtrans-4-aminocyclohexanol (0.0768 mmol, 26.54 mg, 3 eq) and 0.4 mLHunigs base. The reaction was heated in a CEM Discovery microwave vesselat 150° C. for 1.2 hrs. The crude reaction was loaded on a silica gelcolumn and the contents eluted with DCM/MeOH (0-10%) to afford Compound(2) (21 mg). LCMS (ESI) 392 (M+H). 1H NMR (600 MHz, DMSO-d₆) d ppm 1.23(d, J=8.78 Hz, 4H) 1.84 (br. s., 4H) 2.11 (s, 3H) 3.34-3.43 (m, 1H) 3.55(br. s., 2H) 3.72 (br. s., 1H) 4.13 (br. s., 2H) 4.50 (br. s., 1H) 7.03(br. s., 1H) 7.12-7.28 (m, 4H) 7.96 (br. s., 1H) 8.18 (br. s., 1H).

7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using a similar experimental procedure as thatdescribed for the synthesis of7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. LCMS (ESI) 341 (M+H).

Intermediate (IN-2)

Chloro tricyclic amide (IN-2) was synthesized using a similarexperimental procedure as that described for the synthesis of chlorotricyclic amide (IN-1). LCMS (ESI) 223 (M+H)

Compound (3)

To the chloro tricyclic amide (IN-2) (0.035 g, 0.00157 mole) in NMP (1.5mL) was added Hunigs base (0.3 mL) followed by the addition of thetrans-4-aminocyclohexanol (54.2 mg). The reaction mixture was heated at150° C. for 1.5 hrs. The crude reaction was loaded on a silica gelcolumn and the contents eluted with DCM/MeOH (0-10%) to afford Compound(3) (5 mg). LCMS (ESI) 302 (M+H).

tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamateis synthesized by treating 5-Bromo-2,4-dichloropyrimidine withtert-butyl N-(2-amino-2-methyl-propyl)carbamate using similarexperimental conditions as described for the synthesis of tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI)(M+H) 379

tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamateis synthesized by treating tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamatewith 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddbausing similar experimental conditions as described for the synthesis oftert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate LCMS (ESI) (M+H) 427.

tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-2-methyl-propyl]carbamateis synthesized by treating tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamatewith TBAF using similar experimental conditions as described for thesynthesis tert-butylN-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate.LCMS (ESI) (M+H) 427

7-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using a similar experimental procedure as thatdescribed for the synthesis of7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. LCMS (ESI) 369 (M+H).

Intermediate (IN-3)

Chloro tricyclic amide (IN-3) was synthesized using a similar procedureas that described for the synthesis of chloro tricyclic amideIntermediate (IN-1). LCMS (ESI) 251 (M+H).

Compound (4)

Compound (4) was synthesized by treating chlorotricyclic amineIntermediate (IN-3) with trans-4-aminocyclohexanol using similarexperimental conditions as for compound (3). LCMS (ESI) 330 (M+H). 1HNMR (600 MHz, DMSO-d₆) δ ppm 1.07-1.34 (m, 4H) 1.47-2.05 (m, 10H) 3.09(m, 1H) 3.51 (d, J=2.91 Hz, 2H) 3.57 (m, 1H) 4.50 (br. s., 1H) 6.89 (s,1H) 6.94-7.05 (m, 1H) 8.04 (br. s., 1H) 8.60 (s, 1H) 9.00 (br. s., 1H).

benzylN-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]carbamate issynthesized by treating 5-Bromo-2,4-dichloropyrimidine with benzylN-[1-(aminomethyl)propyl]carbamate using similar experimental conditionsas described for the synthesis of tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI)(M+H) 413

benzylN-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]propyl]carbamateis prepared by treating benzylN-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]propyl]-carbamatewith 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddbausing similar experimental conditions as described for the synthesis oftert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate LCMS (ESI) (M+H) 461.

benzylN-[1-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]propyl]carbamateis synthesized by treating benzylN-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]propyl]carbamatewith TBAF using similar experimental conditions as described for thesynthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) (M+H) 461

7-[2-(benzyloxycarbonylamino)butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using a similar experimental procedure as thatdescribed for the synthesis of7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. LCMS (ESI) 403 (M+H).

Intermediate (IN-4)

To a solution of7-[2-(benzyloxycarbonylamino)butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid in dichloromethane was added HBr, the reaction was stirred at 45degrees for 3 hrs. After concentration, 2N NaOH was added to basify(pH=8.0) followed by the addition of THF (20 mL). Boc₂O was then added(1.2 eq) and then contents stirred for 16 hrs. To the crude reactionmixture was then added ethyl acetate (100 mL) and water (50 mL) and theorganic phase was separated, dried (magnesium sulfate) and then concunder vacuum. To the crude product was added dichloromethane (30 mL)followed by DIC and DMAP. After stirring for 2 hrs, TFA was added andthe contents stirred for an hour. The solvents were evaporated undervacuum and the residue basified with satd. NaHCO₃. Ethyl acetate wasthen added and the organic layer separated, dried (magnesium sulfate)and then concentrated under vacuum. Column chromatography withhexane/ethyl acetate (0-100%) afforded the desired chlorotricyclic coreIntermediate (IN-4). LCMS (ESI) 251 (M+H).

Compound (5)

Compound (5) was synthesized by treating chlorotricyclic amineIntermediate (IN-4) with trans-4-aminocyclohexanol using similarexperimental conditions as for compound (3). LCMS (ESI) 330 (M+H). 1HNMR (600 MHz, DMSO-d₆) δ ppm 0.80-0.95 (m, 3H) 1.35-1.92 (m, 10H) 3.66(br. m., 3H) 4.17 (br. s., 2H) 4.47 (br. s., 1H) 6.85 (s, 1H) 6.96 (br.s., 1H) 8.15 (br. s., 1H) 8.62 (br. s., 1H).

tert-butylN-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamatewas synthesized by treating 5-bromo-2,4-dichloropyrimidine withtert-butyl N-[1-(aminomethyl)cyclopentyl]carbamate using similarexperimental conditions as described for the synthesis of tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI)405 (M+H).

tert-butylN-[1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]cyclopentyl]carbamatewas synthesized by treating tert-butylN-[1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]cyclopentyl]carbamatewith 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddbausing similar experimental conditions as described for the synthesis oftert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate LCMS (ESI) 453 (M+H).

tert-butylN-[1-[[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]methyl]cyclopentyl]carbamateis synthesized by treating tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamatewith TBAF using similar experimental conditions as described for thesynthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) 453 (M+H).

7-[[1-(tert-butoxycarbonylamino)cyclopentyl]methyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using a similar experimental procedure as thatdescribed for the synthesis of7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. LCMS (ESI) 395 (M+H).

Intermediate (IN-5)

Chlorotricyclic core Intermediate (IN-5) was synthesized using a similarexperimental procedure as that described for the synthesis of chlorotricyclic amide (IN-1). LCMS (ESI) 277 (M+H).

Compound (6)

Compound (6) was synthesized by treating chlorotricyclic amineIntermediate (IN-5) with trans-4-aminocyclohexanol using similarexperimental conditions as for compound (3). LCMS (ESI) 356 (M+H). 1HNMR (600 MHz, DMSO-d₆) δ ppm 1.08-1.32 (m, 8H) 1.60-2.09 (m, 8H)3.03-3.17 (m, 1H) 3.35 (s, 2H) 3.54-3.62 (m, 1H) 4.51 (d, J=4.39 Hz, 1H)6.88 (s, 1H) 6.96 (br. s., 1H) 8.07 (br. s., 1H) 8.58 (s, 1H).

tert-butylN-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamateis synthesized by treating 5-Bromo-2,4-dichloropyrimidine withtert-butyl N-[(1-aminocyclopentyl)methyl]carbamate using similarexperimental conditions as described for the synthesis of tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. LCMS (ESI)405 (M+H)

tert-butylN-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]methyl]carbamateis synthesized by treating tert-butylN-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamatewith 3,3-diethoxyprop-1-yne in the presence of a catalyst such as Pddbausing similar experimental conditions as described for the synthesis oftert-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4yl]amino]ethyl]carbamate. LCMS (ESI) 453 (M+H).

tert-butylN-[[1-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl]methyl]carbamateis synthesized by treating tert-butylN-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamatewith TBAF using similar experimental conditions as described for thesynthesis tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3d]pyrimidin-7-yl]ethyl]carbamate. LCMS (ESI) 4534 (M+H).

7-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid was synthesized using a similar experimental procedure as thatdescribed for the synthesis of7-[2-(tert-butoxycarbonylamino)ethyl]-2-chloro-5-(o-tolyl)pyrrolo[2,3-d]pyrimidine-6-carboxylicacid. LCMS (ESI) 395 (M+H)

Intermediate (IN-6)

Chloro tricyclic amide (IN-6) was synthesized using a similarexperimental procedure as that described for the chloro tricyclic amideIntermediate (IN-1). LCMS (ESI) 277 (M+H).

Compound (7)

Compound (7) was synthesized by treating chlorotricyclic amineIntermediate (IN-6) with trans-4-aminocyclohexanol using similarexperimental conditions as for compound (3). LCMS (ESI) 356 (M+H). 1HNMR (600 MHz, DMSO-d₆) δ ppm 1.06-1.35 (m, 8H) 1.45-1.95 (m, 8H) 3.10(m, 1H) 3.58 (br. s., 2H) 3.95 (br. s., 1H) 4.49 (br. s., 1H) 6.84 (s,1H) 6.85-6.93 (m, 1H) 8.29 (s, 1H) 8.61 (br. s., 1H).

Each of Intermediates (IN-1) through (IN-6) and corresponding compoundswith various R²⁷, R³¹ and ZZ definitions may be reacted with sodiumhydride and an alkyl halide or other halide to insert the desired R²⁶substitution prior to reaction with an amine, such as described abovefor the synthesis of Compound (1), to produce the desired product offormulae (Q) or (QQ).

Biological Activity

Kinase activity is measured in vitro using electrophoretic mobilityshift assay. The kinase reactions are assembled in 384 well plates intotal volume of 25 μL. The reactions comprise: purified recombinantkinase enzyme, test compound, ATP (at apparent K_(m) for each kinase),and fluorescently labeled peptide substrate. The reaction buffercomposed of: 100 mM HEPES, pH7.5; 5 mM MgCl₂; 1 mM DTT; 0.1% bovineserum albumin; 0.01% Triton X-100, and 1% DMSO (from compound). Thereactions were incubated at room temperature for indicated time andquenched by addition of 45 μL of termination buffer (100 mM HEPES pH7.5;0.01% Triton X-100; 30 mM EDTA). Substrate and product peptides in eachsample were electrophoretically separated and detected using 12 channelLabChip3000® microfluidic capillary electrophoresis instrument (CaliperLife Sciences). The change in the relative fluorescence intensities ofsubstrate and product peaks (reflecting enzyme activity) was measured.Capillary electrophoregramms were analyzed using HTS Well Analyzersoftware (Caliper Life Sciences). The kinase activity in each sample wasdetermined as “product to sum” ratio (PSR): P/(S+P), where P is the peakheight of the product peptide and S is the peak height of the substratepeptide. Negative control samples (0%—inhibition in the absence ofinhibitor) and positive control samples (100%-inhibition, in thepresence of 20 mM EDTA) were assembled in replicates of four and wereused to calculate %-inhibition values for each compound at eachconcentration. Percent inhibition (P_(inh)) was determined usingfollowing equation:P_(inh)=(PSR_(0%)−PSR_(inh))/(PSR_(0%)−PSR_(100%))*100, where PSR_(inh)is the product-sum ratio in the presence of inhibitor, PSR_(0%) is theaverage product-sum ration in the absence of inhibitor and PSR_(100%) isthe average product-sum ratio in 100%-inhibition control samples. TheIC50 values of reference inhibitors were determined by fitting theinhibition curves by a 4 parameter sigmoid dose-response model usingXLfit 4 software (IDBS).

Activity of compounds of the invention is exemplified by the followingtest data:

Kinase* Compd 1 Compd 2 Compd 3 Compd 4 Compd 5 Compd 6 Compd 7Aurora-A + + + ++ + ++ ++++ DYRK3 + + +++ +++ +++ +++ ++++ FMS + + +++++ +++ ++ +++ GSK-3 beta + + +++ ++++ ++++ ++++ ++++ HIPK4 + + +++++++ ++++ ++++ ++++ JNK2 + +++ ++++ ++++ ++++ ++++ ++++ MAPK3 + ++ ++++++ +++ ++++ ++++ MNK2 + + + +++ ++ ++ +++ P38 beta + + + ++ ++ ++ +++*Compounds tested at 10 μM concentration, activity is average of n = 2 +<50% ++ 50-70% +++ 71-90% ++++ >90%

Pharmaceutical Compositions

In one embodiment a pharmaceutical composition comprising one or morecompounds of the invention is provided. In a first aspect, thepharmaceutical composition further comprises one or morepharmaceutically acceptable excipients or vehicles, and optionally othertherapeutic and/or prophylactic ingredients. Such excipients are knownto those of skill in the art. The compounds of the present inventioninclude, without limitation, pharmaceutically acceptable salts and basiccompounds such as free bases. A thorough discussion of pharmaceuticallyacceptable excipients and salts is available in Remington'sPharmaceutical Sciences, 18th Edition (Easton, Pa.: Mack PublishingCompany, 1990). Depending on the intended mode of administration, thepharmaceutical composition may be in the form of solid, semi-solid orliquid dosage forms, such as, for example tablets, suppositories, pills,capsules, powders, liquids, suspensions, creams, ointments, lotions orthe like, preferably in unit dosage form suitable for singleadministration of a precise dosage. The compositions will include aneffective amount of the selected drug in combination with apharmaceutically acceptable carrier and, in addition, may include otherpharmaceutical agents, adjuvants, diluents, buffers, etc.

The invention includes a pharmaceutical composition comprising acompound of the present invention including isomers, racemic ornon-racemic mixtures of isomers, or pharmaceutically acceptable salts orsolvates thereof together with one or more pharmaceutically acceptablecarriers and optionally other therapeutic and/or prophylacticingredients.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate and the like.

For oral administration, the composition will generally take the form ofa tablet, capsule, a softgel capsule nonaqueous solution, suspension orsyrup. Tablets and capsules are preferred oral administration forms.Tablets and capsules for oral use will generally include one or morecommonly used carriers such as lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. Whenliquid suspensions are used, the active agent may be combined withemulsifying and suspending agents. If desired, flavoring, coloringand/or sweetening agents may be added as well. Other optional componentsfor incorporation into an oral formulation herein include, but are notlimited to, preservatives, suspending agents, thickening agents and thelike.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease. A specific disease tobe treated with compounds active against specific kinases is rheumatoidarthritis.

Multi-targeted approach to kinases is becoming an increasingly preferredapproach for the treatment of inflammatory and cancer diseases toovercome resistance of single agent therapies. The present inventionaims at combination therapy involving two or more protein kinasetargets. For example, regorafenib, a multikinase inhibitor, given as asingle agent to patients with treatment-refractory metastatic colorectalcancer, significantly improved overall survival and delayed diseaseprogression in an international phase III trial.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to one of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the invention as defined in the appended claims.

What is claimed is:
 1. A compound of formula (Q):

or a pharmaceutically acceptable salt thereof; wherein R²⁶ is H; eachR³¹ is independently aryl, alkyl, or cycloalkyl, wherein two R³¹s onadjacent ring atoms or on the same ring atom together with the ringatom(s) to which they are attached optionally form a 3-8-membered cycle;yy is 2; ZZ is —(CH₂)_(xx)— wherein xx is 1, 2, 3, or 4; R⁵⁵ is NHR^(A),wherein R^(A) is unsubstituted C₁-C₈ alkyl, cycloalkylalkyl, -TT-RR,C₁-C₈ cycloalkyl, or heterocycloalkyl containing atoms selected from N,O, or S; TT is C₁-C₈ alkyl or C₃-C₈ cycloalkyl linker; RR is a hydroxyl,C₁-C₆ alkoxy, amino, C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₆-C₁₀ aryl,heteroaryl comprising one or two 5- or 6-member rings and 1-4heteroatoms selected from N, O, or S, C₃-C₁₀ carbocycle, or heterocyclecomprising one or two 5- or 6-member rings and 1-4 heteroatoms selectedfrom N, O or S; R²⁷ is -(alkylene)_(m)-C₃-C₈ cycloalkyl,-(alkylene)_(m)-heterocyclo, or C₁-C₃ alkyl; and m is 0 or
 1. 2. Thecompound of claim 1, wherein two R³¹s on adjacent ring atoms or on thesame ring atom together with the ring atom(s) to which they are attachedform a 3-8-membered cycle.
 3. The compound of claim 1, wherein two R³¹son the same ring atom together with the ring atom to which they areattached form a 3-8 membered cycle.
 4. The compound of claim 3, whereinthe 3-8 membered cycle is a 5 membered cycle.
 5. The compound of claim3, wherein the 3-8 membered cycle is a 6 membered cycle.
 6. The compoundof claim 1, having the formula:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim6, wherein two R³¹s on adjacent ring atoms or on the same ring atomtogether with the ring atom(s) to which they are attached form a3-8-membered cycle.
 8. The compound of claim 6, wherein two R³¹s on thesame ring atom together with the ring atom to which they are attachedform a 3-8 membered cycle.
 9. The compound of claim 1, wherein ZZ isselected from the group consisting of —CH₂— and —CH₂CH₂—.
 10. Thecompound of claim 1, wherein R³¹ is selected from the group consistingof methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.
 11. The compound of claim 1, wherein R⁵⁵ isselected from the group consisting of cis 4-hydroxycyclohexylamino,trans 4-hydroxycyclohexylamino, cyclohexylamino, cyclopentylamino, andstraight chain C alkylamino.
 12. The compound of claim 11, wherein yy is2.
 13. The compound of claim 12, wherein two R³¹s on adjacent ring atomsor on the same ring atom together with the ring atom(s) to which theyare attached form a 3-8-membered cycle.
 14. The compound of claim 12,wherein R³¹ is selected from the group consisting of methyl, ethyl,n-propyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.
 15. A pharmaceutical composition comprising an effectiveamount of the compound of claim 1 in a pharmaceutically acceptablecarrier.
 16. A pharmaceutical composition comprising an effective amountof the compound of claim 6 in a pharmaceutically acceptable carrier.